HK1049169B

HK1049169B - Substituted 4-benzylaminoquinolines, process for their preparation, pharmaceuticals containing these compounds and use thereof

Info

Publication number: HK1049169B
Application number: HK03101156.5A
Authority: HK
Inventors: A‧霍夫梅斯特; E‧福克; H-W‧克里曼; H-W‧詹森; M‧毕克尔; M‧畢克爾
Original assignee: 萨诺费－阿文蒂斯德国有限公司; 薩諾費-阿文蒂斯德國有限公司
Priority date: 1999-09-22
Filing date: 2000-09-06
Publication date: 2005-04-22
Also published as: EP1218401A1; PT1218401E; HK1049169A1; DE50006842D1; BR0014233A; HUP0203045A3; DK1218401T3; AU7515600A; NZ517899A; RU2247125C2; US6339077B1; JP4833471B2; EE200200143A; WO2001021642A1; JP2003510255A; HUP0203045A2; ATE269352T1; ES2218222T3; CA2385445A1; KR20030010575A

Abstract

The invention relates to substituted 4-benzylaminoquinolines and their hetero analogs, and to the pharmaceutically acceptable salts and physiologically functional derivatives thereof. Compounds of formula Iin which the radicals are defined in the specification, and their physiologically tolerated salts, physiologically functional derivatives and processes for their preparation are described. The compounds are suitable, for example, as medicines for the prophylaxis or treatment of gallstones.

Description

substituted 4-benzylaminoquinolines, method for the production thereof, medicaments containing these compounds and the use thereof

Technical Field

The present invention relates to substituted 4-benzylaminoquinolines, and their isoanalogs, pharmaceutically acceptable salts, and physiologically functional derivatives.

Background

In addition to a number of factors, the formation of gallstones depends essentially on the composition of the bile, in particular the concentrations and proportions of cholesterol, phospholipids and bile salts. A prerequisite for the formation of cholesterol gallstones is the presence of bile which is supersaturated with cholesterol (see Carey, M.C. and Small, D.M. (1978) 'physicochemical Properties of the solubility of cholesterol in bile. relationship between gallstone formation and dissolution in humans,' J.Clin.invest.61: 998-.

Until now, gallstones have been removed mainly by surgical methods, and therefore, there is a great medical need for drugs for dissolving gallstones and preventing the formation of gallstones.

Disclosure of Invention

It is an object of the present invention to provide compounds that prevent gallstone formation by preventing cholesterol from becoming supersaturated in bile, or by delaying the formation of cholesterol crystals from supersaturated bile.

The present invention includes compounds of formula I and pharmaceutically acceptable salts and physiologically functional derivatives thereof:

wherein:

g is

K is-OR (7), -NR (7) R (8), -HN-CH₂-CH₂-CO₂H、-HN-CH₂-CH₂-SO₃H、-NH-CH₂-CO₂H、-N(CH₃)CH₂CO₂H、-HN-CHR(9)CO₂H. or-Ocat, wherein cat is a cation such as an alkali or alkaline earth metal ion or a quaternary ammonium ion;

r (7) and R (8) are independently selected from hydrogen and (C)₁-C₄) -alkyl radicalPhenyl or benzyl, wherein the benzene nucleus may be F, C1, CF₃Methyl, methoxy up to 3 times;

r (9) is (C)₁-C₄) -alkyl, benzyl, -CH₂-OH、H₃CSCH₂CH₂-、HO₂CCH₂-、HO₂CCH₂CH₂-；

R (1) -R (6) are independently selected from hydrogen, -OR (10), -SR (10), -NR (10) R (13), -OCOR (10), -SCOR (10), -NHCOR (10), -OPO (OR (10))₂、-OSO₂OR (10), -R (10), R (1) and R (2), R (3) and R (4), R (5) and R (6) together form the oxygen of a carbonyl group, exactly one group among R (1) -R (6) always having the meaning of a bond to L;

r (10) and R (13) are independently selected from hydrogen and (C)₁-C₄) Alkyl, phenyl or benzyl, where the benzene nucleus may be replaced by F, Cl, CF₃Methyl, methoxy up to 3 times;

l is (C)₁-C₁₅) -alkyl, wherein one or more CH₂The units may be substituted by-CH- ═ CH-, -C.ident.C-, -NR (11) -, -CO-, -O-, -SO₂-, or-S-substitution;

r (11) is hydrogen, (C)₁-C₈) -alkyl, R (12) -CO-, phenyl, or benzyl;

r (12) is hydrogen, (C)₁-C₈) Alkyl, phenyl and benzyl, where the benzene nucleus may be replaced by F, Cl, CF₃Methyl, methoxy up to 3 times;

p is

Or

Wherein

A is N or CH;

b is N or CH;

d is N or CH;

e is N or CH;

r (16) -R (24) are independently selected from hydrogen, F, Cl, Br, I, (C)₁-C₄) -alkyl, wherein said alkyl may be substituted one or more times by fluorine, or CN, NO₂、NR(25)R(26)、OR(25)、OCOR(25)、COR(25)、COOR(25)、CONR(25)R(26)、SO₂R(25)、SO₂OR (25), and SO₂NR (25) R (26), wherein all of R (16) to R (24) have the meaning of a bond to L; and is

R (25) and R (26) are independently selected from hydrogen and (C)₁-C₄) -alkyl, wherein the alkyl may be substituted one or more times by fluorine, or phenyl and benzyl.

Compounds of the formula I in which one or more radicals have the meanings indicated below and their pharmaceutically acceptable salts and physiologically functional derivatives are preferred,

g is

K is-OR (7), -NR (7) R (8), -HN-CH₂-CH₂-CO₂H、-HN-CH₂-CH₂-SO₃H、-NH-CH₂-CO₂H、-N(CH₃)CH₂CO₂H、-HN-CHR(9)CO₂H. -Ocat, wherein cat is a cation such as an alkali or alkaline earth metal ion or a quaternary ammonium ion;

r (7) and R (8) are independently selected from hydrogen and (C)₁-C₄) Alkyl, phenyl or benzyl, where the benzene nucleus may be replaced by F, Cl, CF₃Methyl, methoxy up to 3 times;

R (1), R (3), R (5) are independently selected from hydrogen, -OR (10), -NR (10) R (13), -OCOR (10), -NHCOR (10);

l is (C)₁-C₈) -alkyl, wherein one or more CH₂The units may be substituted by-CH- ═ CH-, -C.ident.C-, -NR (11) -, -CO-, -O-, or-SO₂-substitution;

r (11) is hydrogen, (C)₁-C₄) -alkyl, R (12) -CO-, phenyl, benzyl;

r (12) is hydrogen, (C)₁-C₄) Alkyl, phenyl and benzyl, where the benzene nucleus may be replaced by F, Cl, CF₃Methyl, methoxy up to 3 times;

p is

Wherein

A is N or CH;

b is N or CH;

r (16) -R (24) are independently selected from hydrogen, F, Cl, Br, (C)₁-C₄) -alkyl, wherein said alkyl may be substituted one OR more times by fluorine, OR is NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), wherein all of the radicals R (16) -R (24) have the meaning of a bond to L;

r (25) and R (26) are independently selected from hydrogen and (C)₁-C₄) -alkyl, wherein the alkyl may be substituted one or more times by fluorine, or phenyl, benzyl.

Compounds of the formula I in which one or more radicals have the meanings indicated below and the pharmaceutically acceptable salts thereof are particularly preferred,

g is

K is-OR (7), -NR (7) R (8), -HN-CH₂-CH₂-CO₂H、-HN-CH₂-CH₂-SO₃H、-NH-CH₂-CO₂H、-N(CH₃)CH₂CO₂H. -Ocat, wherein cat is a cation such as an alkali or alkaline earth metal ion or a quaternary ammonium ion;

r (1) is hydrogen, -OH;

l is (C)₁-C₅) -alkyl, wherein one or more CH₂The units may be substituted by-CH- ═ CH-, -C.ident.C-, -NR (11) -, -CO-, -O-, or-SO₂-substitution;

r (11) is hydrogen, (C)₁-C₄) -alkyl, R (12) -CO-, phenyl, benzyl;

p is

R (16) -R (24) are independently selected from hydrogen, F, Cl and (C)₁-C₄) -alkyl, wherein the alkyl may be substituted one OR more times by fluorine, OR is NR (25) R (26), OR (25)OCOR (25), COR (25), COOR (25), CONR (25) R (26), all of which groups R (16) -R (24) have the meaning of a bond to L;

Compounds of the formula I in which one or more radicals have the meanings indicated below and the pharmaceutically acceptable salts thereof are very particularly preferred,

g is

R (1) is hydrogen, -OH;

p is

Wherein

R (16) -R (24) are independently selected from hydrogen, F, Cl and (C)₁-C₄) -alkyl, wherein said alkyl may be substituted one OR more times by fluorine, OR is NR (25) R (26), OR (25), OCOR (25), COR (25), COOR (25), CONR (25) R (26), wherein all of the radicals R (16) -R (24) have the meaning of a bond to L;

If the compounds of the formula I contain one or more asymmetric centers, they may have the S or R configuration. The compounds of the present invention may be in the form of optical isomers, diastereomers, racemates or mixtures thereof.

The expression "wherein said alkyl group may be substituted one or more times by fluorine" also includes perfluorinated alkyl groups.

The defined alkyl groups may be straight or branched.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical use because they have better solubility in water than the starting or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the novel compounds of the invention are inorganic acid salts such as the hydrochloride, hydrobromide, phosphate, metaphosphate, nitrate, sulfonate and sulfate salts, and organic acid salts such as acetate, benzenesulfonate, benzoate, citrate, ethanesulfonate, fumarate, gluconate, glycolate, isethionate, lactate, lactobionate, maleate, malate, methanesulfonate, succinate, p-toluenesulfonate, tartrate and trifluoroacetate salts. For pharmaceutical applications, the hydrochloride salt is particularly preferably used. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts).

Salts with non-pharmaceutically acceptable anions are also within the scope of the invention, as they are useful as intermediates in the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic, e.g. in vitro, administration.

The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of the novel compounds of formula I, such as an ester, which upon administration to a mammal, such as a human, is capable of forming (directly or indirectly) a compound of formula I or an active metabolite thereof.

Physiologically functional derivatives include prodrugs of the novel compounds. Such prodrugs can be metabolized in vivo to form new compounds. These prodrugs may or may not be active themselves.

The compounds of the present invention may also exist in various forms, for example, in amorphous and various crystalline forms. All forms of the compounds of the invention are part of the invention and are an aspect of the invention.

Hereinafter, "compound of formula (I)" refers to the above-mentioned compound of formula (I), and salts, solvates and physiologically functional derivatives thereof.

The amount of a compound of formula (I) required to achieve a desired biological effect depends on a variety of factors, such as the particular compound selected, the intended application, the mode of administration, and the clinical condition of the patient.

The daily dose is generally in the range 0.1mg to 100mg (typically 0.1mg to 50mg) per day per kg body weight, for example 0.1 to 10 mg/kg/day. Tablets or capsules may contain, for example, 0.01 to 100mg, typically 0.02 to 50 mg. For pharmaceutically acceptable salts, the above weight data refer to the weight of the salt of the compound of formula I. For the prevention or treatment of the above conditions, the compounds of formula (I) may be used as the compounds themselves, but are preferably used in the form of pharmaceutical compositions containing compatible carriers. Of course, the carrier must be compatible with the other components of the composition and not deleterious to the health of the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a single dose, for example as a tablet containing from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may also be present, including additional compounds of formula (I). The pharmaceutical compositions of the invention can be prepared by a known pharmaceutical process which essentially consists in mixing the active ingredient with pharmaceutically acceptable carriers and/or excipients.

The novel pharmaceutical compositions of the present invention are those suitable for oral and peroral (e.g. sublingual) administration, but the most suitable route of administration for each case will depend on the nature and severity of the condition being treated and on the nature of the particular compound of formula (I) used. The invention also includes coated preparations and coated sustained-release preparations. Formulations resistant to acid and gastric fluid are preferred. Suitable coatings that are resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and anionic polymers of methyl methacrylate.

Suitable orally administrable compounds may be in the form of discrete units, such as capsules, cachets, lozenges, or tablets, each of which contains a defined amount of a compound of formula (I); as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As noted above, these compositions may be prepared by any suitable pharmaceutical method which includes admixing the active ingredient with a carrier, which may include one or more other ingredients. The compositions are generally prepared by uniformly mixing the active ingredient with a liquid and/or finely divided solid carrier and then setting the product as desired. Thus, for example, tablets may be prepared by compressing or shaping powders or granules of the compound, optionally together with one or more other ingredients. Compressed tablets may be prepared by tableting the compound in a free-flowing form, for example in powder or granule form, if appropriate in admixture with a binder, lubricant, inert diluent and/or one (or more) surfactant/dispersant in a suitable machine. Shaped tablets may be made by shaping in a suitable machine a compound which is in powder form and which has been moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for oral (sublingual) administration include suckable tablets containing a compound of formula I and a flavoring agent, usually sucrose and acacia or tragacanth, and lozenges comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

The invention also relates to two methods for preparing the compound of formula I.

Method A) this method requires a Pd (O) -catalyzed coupling of a compound of the formula IIId, where X is, for example, Br or I, with a compound of the formula IId. The HX thus liberated is captured by an auxiliary base, such as triethylamine or pyridine.

R1, R3, R4, R5, K and P are as defined above. Acetylene-bile acid derivatives of formula IId are prepared from the appropriate bile acid ketones. In this regard, lithium acetylide was added to ketocholic acid in a manner similar to known methods (U.S. patent 5,641,767).

Method B) carboxylic acids of the formula IIIe (R ═ OH) are reacted with compounds of the formula IIe according to known methods in the presence of suitable coupling agents such as TOTU (ChemikerZeitung, 98(1974), 817), DCC/HOBt (j.am. chem. so., 77(1955), 1067) or CMC/HOBt (j.org. chem., 21(1956), 439) (see abbreviations below) to form amide bonds. The amides of formula I can also be prepared by reacting the activated carboxylic acid derivative IIIe with a compound of formula IIe in the presence of an auxiliary base (e.g. triethylamine or pyridine) in a manner known to those skilled in the art. Activated carboxylic acid derivatives which may be mentioned are, for example, the corresponding chlorides (R ═ Cl), imidazoles (R ═ 1-imidazolyl; angelw.chem.int.ed.engl., 1(1962), 351), or mixed anhydrides with Cl-COOEt or tosyl chloride.

R1, R3, R4, R5, K and P are as defined above. The 3-ethanolamine-bile acids of the formula IIe are prepared by known methods (Tetrahedron Lett., 34(1993), 817).

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives have a beneficial effect on the composition of bile and can prevent gallstone formation by preventing supersaturation of cholesterol in the bile or by delaying the formation of cholesterol crystals from supersaturated bile. The compounds of the invention may be used alone or in combination with lipid-lowering active ingredients (see Rote Liste, chapter 58). The compounds of the invention are particularly suitable for the prevention and treatment of gallstones.

The novel compounds of formula (I) enter the hepatobiliary system and thus play a role in these tissues. Thus, the absorption of water from the gall bladder is inhibited by inhibiting reverse transport of gallbladder epithelial subtype 3 apical NHE, thereby diluting the bile.

The biological effects of the novel compounds of the invention were tested by determining the inhibition of sodium/proton exchanger subtype 3.

1. Description of the test

The remaining activity of the human NHE-3 protein (expressed in LAP1 cell line) was determined as follows: determination of intracellular pH (pH) after acidification_i) The healing effect is initiated when NHE is able to perform its function, even in the absence of bicarbonate. For this, the pH was determined using the pH-sensitive fluorescent dye BCECF (Calbiochem, using a precursor of BCECF-AM)_i. Cells were first loaded with BCECF. BCECF fluorescence was measured in a "proportional fluorescence spectrometer" (Photon Technology International, South Brunswick, N.J., USA) with excitation wavelengths of 505 and 440 nm, emission wavelength of 535 nm, and converted to pH using a calibration plot_i. Placing the cells in NH₄Cl buffer (pH 7.4) (NH)₄Cl buffer solution: 115mM NaCl, 20mM NH₄Cl，5mM KCl，1mM CaCl₂，1mM MgSO₄20mM HEPES, 5mM glucose, 1mg/ml BSA; adjusted to pH 7.4 with 1M NaOH), even during BCECF loading. By adding 975. mu.l NH-free₄Cl buffer (see below) was added to a 25. mu.l aliquot in NH₄Intracellular acidification was induced in cells cultured in Cl buffer. The rate of pH recovery after 3 minutes was recorded. To calculate the inhibitory potency of the test substance, cells are first assessed in a buffer in which no pH recovery at all or at all occurred. For complete pH recovery (100%), cells were incubated in the presence of Na⁺Buffer (133.8mM NaCl, 4.7mM KCl, 1.25mM CaCl)₂，1.25mM MgCl₂，0.97mM Na₂HPO₄，0.23mM NaH₂PO₄5mM HEPES, 5mM glucose, adjusted to pH 7.0 with 1M NaOH). To determine the 0% value, cells were incubated in the absence of Na⁺Buffer (133.8mM choline hydrochloride, 4.7mM KCl, 1.25mM CaCl)₂，1.25mM MgCl₂，0.97mM K₂HPO₄，0.23mM KH₂PO₄5mM HEPES, 5mM dextranGlucose, adjusted to pH 7.0 with 1 MNaOH). In the presence of Na⁺The test substance was prepared in the buffer of (1). The recovery of intracellular pH at the test concentration of the substance is expressed as the maximum recovery percentage.

As a result:

example 1: residual activity at 20. mu.M hNHE 3%

Example 2: residual activity at 20. mu.M hNHE 3%

Example 3: residual activity at 20. mu.M hNHE 3%

Example 6: residual activity at 20. mu.M hNHE 3%

Example 11: residual activity at 20. mu.M hNHE 3%

Example 13: residual activity at 20. mu.M hNHE 3%

Example 14: residual activity at 20. mu.M hNHE 3%

Example 15: residual activity at 20. mu.M hNHE 3%

Example 16: residual activity at 20. mu.M hNHE 3%

Example 17: residual activity at 20. mu.M hNHE 3%

Example 18: residual activity at 20. mu.M hNHE 3%

Example 20: residual activity at 20. mu.M hNHE 3%

Example 23: residual activity at 20. mu.M hNHE 3%

Example 24: residual activity at 20. mu.M hNHE 3%

Example 25: residual activity at 20. mu.M hNHE 3%

Example 26: residual activity at 20. mu.M hNHE 3%

Example 27: residual activity at 20. mu.M hNHE 3%

Example 28: residual activity at 20. mu.M hNHE 3%

Example 29: residual activity at 20. mu.M hNHE 3%

Example 30: residual activity at 20. mu.M hNHE 3%

Example 31: residual activity at 20. mu.M hNHE 3%

List of abbreviations:

me methyl group

LAH lithium aluminum hydride

DMF N, N-dimethylformamide

EI electron impact

CI chemical ionization

RT Room temperature

EA Ethyl acetate

mp melting point

HEP n-heptane

DME dimethoxyethane

ES electronic spray

FAB fast atom bombardment

THF tetrahydrofuran

eq. equivalent

TOTU O- [ (ethoxycarbonyl) cyanomethyleneamino ] -N, N, N ', N' -tetramethyluronium tetrafluoroborate

HOBt 1-hydroxybenzotriazole

CMC N-cyclohexyl-N' - (2-morpholinylethyl) carbodiimide methyl p-toluenesulfonate

DCC dicyclohexylcarbodiimide

Detailed Description

The following examples are intended to illustrate the invention in more detail without limiting the invention to the products and embodiments described in the examples.

Example 1

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

The synthesis route is as follows:

a)3, 7, 12-Triacetyl cholic acid methyl ester

90g of cholic acid methyl ester and 3.0g of dimethylaminopyridine were dissolved in 500ml of pyridine, and after 500ml of acetic anhydride was added, the mixture was stirred at room temperature overnight. The mixture was poured into ice water and extracted with ethyl acetate (3 ×). Drying (MgSO)₄) The organic phase was evaporated, yielding 92g of methyl 3, 7, 12-triacetylcholine, ms (fab): m⁺+Li＝555。

b)7, 12-diacetylcholic acid methyl ester

150ml of acetic anhydride were slowly added dropwise to 1.5L of methanol at 5 ℃. After 15 minutes, 92g of methyl 3, 7, 12-triacetylcholine were added and the mixture was stirred at room temperature for 1 hour. Pour it into ice water and extract with ethyl acetate (3 ×). Dissolving the organic phase with 1N sodium carbonateThe solution was washed, dried over magnesium sulfate and evaporated. 85g of crude product were obtained, MS (FAB): m⁺+Li＝513。

c) 3-keto-7, 12-diacetylcholic acid methyl ester

85g (168mmol) of methyl 7, 12-diacetylcholate, 183.7g of pyridinium chlorochromate and 175g of molecular sieve are stirred in 2.5L of dichloromethane at room temperature for 2 hours. The mixture was poured into 7L of diethyl ether and the solid was filtered off. The solvent was evaporated and the residue was dissolved in ethyl acetate. Chromatography on a Florisil column gave 59.6g of product, ms (fab): m⁺+Li＝511。

d)3 beta-ethynyl-7, 12-diacetylcholic acid methyl ester

Acetylene was passed through 750ml of anhydrous tetrahydrofuran at-55 ℃ for 25 minutes under an argon atmosphere. To the solution was added dropwise 145ml of a 15% n-butyllithium solution in hexane, followed by stirring for 10 minutes. 45g (89mmol) of methyl 3-keto-7, 12-diacetylcholate are added and the mixture is stirred at-40 ℃ for 1.5 h. For work-up, 500ml of saturated aqueous ammonium chloride solution were added, extracted with ethyl acetate (3 ×), and the organic phase was dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel (n-heptane/ethyl acetate 1: 1). 35.3g of product, MS (FAB): m⁺+Li＝537。

e)3 beta-ethynyl cholic acid

35.2g (66mmol) of the product obtained in step d) are dissolved in 1L of methanol, 300ml of 2N sodium hydroxide solution are added and the mixture is refluxed for 25 hours. The solvent was evaporated, the residue was dissolved in water and acidified to pH 2 with 2N hydrochloric acid. The precipitate was filtered off and washed with water to neutrality. The residue was dried to yield 14.6g of product, ms (fab): m⁺+ Li-439. Intermediate 2: 2-methyl-3- (acetyl-1-yl) -4- (4-bromobenzyl) aminoquinoline

Synthetic route

a)2- (1-methyl-3-oxo-but-1-enylamino) benzonitrile is prepared from 2-aminobenzonitrile by standard methods (eur. Pat. appl., C07D 215/42; med chem, 31(1988), 1278); yellow solid, melting point: 100 ℃; ms (ci): m⁺+H＝201。

b)1- (4-amino-2-methylquinolin-3-yl) ethanone from 2- (1-methyl-3-oxobut-1-enylamino) benzonitrile by reaction with CuCl and K₂CO₃Cyclization (j.med.chem., 31(1988), 1278) or NaOMe-promoted known methods (eur.pat.appl., C07D 215/42); a yellow solid; MS (Cl): m⁺+H＝201。

c)1- (4- (4-bromobenzylamino-2-methylquinolin-3-yl) ethanone

In the presence of 75ml of CH₂Cl₂And 55ml of 50% strength NaOH, 1.8g of 1- (4-amino-2-methylquinolin-3-yl) ethanone are mixed with 0.15 equivalent of tetramethylammonium hydrogensulfate and stirred vigorously at room temperature for 30 minutes. 1.1 equivalents of 4-bromobenzyl bromide were then added and the mixture was stirred vigorously at room temperature for 4-5 hours. For work-up, the two phases are separated, the aqueous phase is extracted 2 times with dichloromethane, and the combined organic phases are washed 2 times with water and dried over magnesium sulfate. The solvent was removed by distillation and the residue was purified by chromatography on silica gel (300 g; CH)₂Cl₂MeOH 98: 2) to yield the title compound as a colorless glassy solid. MS (ES +): m⁺+H＝369，

General procedure for carrying out Pd (0) -catalyzed coupling reactions

The bromoaryl compound (1.0eq) and bile acid-acetylene (1.5eq) were added to DMF/triethylamine (2: 1) and the solution was degassed. After purging with argon, 0.1eq Pd (PPH) was added₃)₂Cl₂And 0.1eq CuI, and the reaction solution was heated to 80 ℃. Depending on the progress of the reaction, it may be expedient to add further catalyst or to raise the temperature further, up to 100 ℃. For working up, the solvent is removed by chromatography on silica gelPurifying the obtained crude product with CH₂Cl₂The MeOH mixture elutes.

The reaction was carried out by this general method and after 21 hours at 100 ℃ a yellow orange solid was obtained, melting point: 178 ℃ (decomposition), MS (ES +): m⁺+H＝772。

Example 2:

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) eth-2-yl ] benzyl } aminoquinoline

The product from example 1 was dissolved in 1: 1 ethanol/methanol and after addition of Pd/C (10%), shaken under hydrogen until the conversion was complete. The Pd catalyst was removed by filtration and the solvent was removed by distillation to give the hydrogenation product as crystals as a pale yellow solid. Melting point: 172 ℃ (decomposition); MS (ES +): m⁺+H＝726。

Example 3:

2-methyl-4-aminobenzylquinoline-3-carboxylic acid N- {2-O- [7 α, 12 α -dihydroxy-10 β, 13 β -dimethyl-17 β - (methylvalerate-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3 β -yl ] ethylamide

Preparing an intermediate:

intermediate 1: 3 beta-O- (1-aminoeth-2-yl) cholic acid methyl ester

The title compound is prepared from cholic acid in 6 steps according to methods known in the literature (Tetrahedron Lett., 33(1992), 195; Tetrahedron Lett., 34(1993), 817).

Intermediate 2: 4-benzylamino-2-methylquinoline-3-carboxylic acid

The synthesis route is as follows:

a) methyl 4-amino-2-methylquinoline-3-carboxylate is prepared by methods known to the skilled worker (Tetrahedron, 51(1995), 12277). MS (Cl): m⁺+H＝217。

b) 4-benzylamino-2-methylquinoline-3-carboxylic acid methyl ester was prepared from 4-amino-2-methylquinoline-3-carboxylic acid methyl ester and benzyl bromide by the same procedure as for the preparation of 1- (4- (4-bromobenzylamino-2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). MS (ES)⁺)：M⁺+H＝307。

c) 4-benzylamino-2-methylquinoline-3-carboxylic acid is prepared by hydrolysis of the above methyl ester with KOH (5eq) in ethanol solution. After the conversion was complete, the solvent was removed and the crude product was taken up in 2N NaOH. The aqueous solution was extracted with dichloromethane, the phases separated and the aqueous phase neutralized with 2N HCl, and the title compound precipitated. Filtered and dried to obtain a colorless solid. Melting point: 190 ℃; MS (Cl): m⁺+H＝293，M⁺-CO₂＝249。

2-methyl-4-aminobenzylquinoline-3-carboxylic acid N- {2-O- [7 α, 12 α -dihydroxy-10 β, 13 β -dimethyl-17 β - (methylvalerate-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3 β -yl ] ethylamide trifluoroacetate

Placing intermediate 1(1.0eq) and intermediate 2(1.0eq) inTo DMF, 1.0 equivalent of HOBt was added, followed by addition of a 1.1 equivalent CMC in DMF at 0 ℃. If desired, additional CMC and/or elevated temperature may be added to achieve 60 deg.C. For work-up, the solvent was removed, the residue taken up in ethyl acetate and washed 2 times with saturated sodium bicarbonate. The sodium bicarbonate phase was extracted 1 more time with ethyl acetate and the combined organic extracts were washed 2 times with water, dried over magnesium sulfate and evaporated. The crude product obtained was purified by preparative HPLC to give the title compound as a light yellow solid. Melting point: 102 ℃; MS (ES +): m⁺+H＝741。

Example 4

2-methyl-4-aminobenzylquinoline-3-carboxylic acid N- {2-O- [7 α, 12 α -dihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3 β -yl ] } ethylamide

The product of example 3 was mixed with 5.0 equivalents of KOH in methanol/H₂O mixture and stirred at a temperature between room temperature and 50 ℃. Additional KOH was added, if necessary, until conversion was complete. The solvent was then removed and the residue was taken up in water and neutralized with 1N HCl. The resulting precipitate was filtered off and then dried to give the product as a colorless solid. Melting point: 143 ℃; MS (ES +): m⁺+H＝727。

Example 5

2-methyl-4-aminobenzylquinoline-3-carboxylic acid N- {2-O- [7 α, 12 α -dihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid N- (2-sulfonic acid) ethylamide-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3 β -yl ] } ethylamide trifluoroacetate salt

85mg of the product obtained in example 3 are dissolved in 5ml of anhydrous DMF. At 0Adding 0.016ml NEt at DEG C₃In 1ml of anhydrous DMF and 1.0 equivalent of TOTU dissolved in 2ml of anhydrous DMF was added. After stirring at a temperature between 0 ℃ and room temperature for 1 hour, the resulting solution was added to 1.0 equivalent of taurine, 1ml of NEt₃、2ml H₂O and 2ml DMF and stirring was continued. For work-up, the reaction mixture was concentrated and purified by preparative HPLC to give the title compound as a pale yellow solid. Melting point: 180 ℃; MS (ES +): m⁺+H＝834。

Example 6

Methyl 2-methyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylate:

preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid methyl ester

The synthesis route is as follows:

a) methyl 4-amino-2-methylquinoline-3-carboxylate is prepared by methods known to those skilled in the art (Tetrahedron51(1995), 12277).

b)4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid methyl ester was prepared from 4-amino-2-methylquinoline-3-carboxylic acid methyl ester and 4-bromobenzyl bromide according to the same procedure as described for the preparation of 1- (4- (4-bromobenzylamino-2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). Melting point: 89 ℃; MS (ES +): 385/387.

Methyl 2-methyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylate was prepared by the general procedure described above (see example 1). Melting point: 165 ℃; ms (fab): 737.

example 7

2-methyl-4- {4- [1- (3 α,7 α, 12 α, trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylic acid n-butyl ester

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid n-butyl ester

The synthesis route is as follows:

a)4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid n-butyl ester

200mg (1.0eq) of methyl 4- (4-bromobenzylamino) -2-methylquinoline-3-carboxylate (cf. example 5) are dissolved in an n-butanol/THF mixture, 2.5 equivalents of NaH (55%) are added at room temperature, and the mixture is stirred for 2 hours with the exclusion of water. For work-up, the solvent was removed and the residue was taken up in dichloromethane. Washed with water and the aqueous phase was extracted 1 more time with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. Purification by silica gel chromatography (ethyl acetate/n-heptane 1: 1 → 4: 1) afforded the ester product as a colorless solid. Melting point: 116 ℃; MS (ES +): 427/429.

N-butyl 2-methyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylate was prepared by the general procedure described above (see example 1). Melting point: 70 ℃; ms (fab): 779.

example 8

2-methyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethyne-2-yl ] benzyl } aminoquinoline-3-carboxylic acid isopropyl ester

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid isopropyl ester

The synthesis route is as follows:

a)4- (4-Bromobenzylamino) -2-methylquinoline-3-carboxylic acid isopropyl ester is prepared analogously

Procedure for 4- (4-bromobenzylamino) -2-methylquinoline-3-carboxylic acid n-butyl ester (see example 6), prepared by transesterification of the corresponding methyl ester mixture in an isopropanol/THF mixture, gives the title compound as a colorless oil. MS (ES +): 413/415.

Isopropyl 2-methyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylate was prepared by the general procedure described above (see example 1). 150 ℃; ms (fab): 765.

example 9

2-methyl-4-benzylamino-6- {2- [3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl ] ethynyl-1-yl } quinoline-3-carboxylic acid methyl ester

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

The synthesis route is as follows:

a) 5-bromo-2-aminobenzonitrile was prepared according to methods known in the literature (Synlett., 1994, 450); ms (ci): 197/199.

b) Methyl 6-bromo-4-amino-2-methylquinoline-3-carboxylate is prepared according to methods known to those skilled in the art (Tetrahedron51(1995), 12277).

c) 6-bromo-4-benzylamino-2-methylquinoline-3-carboxylic acid methyl ester was prepared from 6-bromo-4-amino-2-methylquinoline-3-carboxylic acid methyl ester and 4-bromobenzyl bromide following the same procedure as for the preparation of 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). Melting point: 89 ℃; MS (ES +): 385/387.

Methyl 2-methyl-4-benzylamino-6- {2- [3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] -phenanthren-3-yl ] ethynyl-1-yl } quinoline-3-carboxylate was prepared by the general procedure described above (see example 1). Melting point: 223 ℃ (decomposition); MS (ES +): 737.

example 10

2-methyl-4-benzylamino-6- {2- [3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl ] eth-1-yl } quinoline-3-carboxylic acid methyl ester

The product described in example 8 was hydrogenated in analogy to the procedure in example 2, to yield the title compound as light yellow solid. Melting point: > 185 ℃ (decomposition); ms (fab): 741.

example 11

2, 5-dimethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethyne-2-yl ] benzyl } aminoquinoline-3-carboxylic acid methyl ester

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 4- (4-Bromobenzylamino) -2, 5-dimethylquinoline-3-carboxylic acid methyl ester

The synthesis route is as follows:

a) methyl 4-amino-2, 5-dimethylquinoline-3-carboxylate was prepared in a manner known to the skilled person in analogy to the procedure described in intermediate 2a, example 6 (Tetrahedron51(1995), 12277).

b)4- (4-Bromobenzylamino) -2, 5-dimethylquinoline-3-carboxylic acid methyl ester was prepared from 4-amino-2, 5-dimethylquinoline-3-carboxylic acid methyl ester and 4-bromobenzyl bromide by the same procedure as described for the preparation of 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). Melting point: 150 ℃; MS (Cl +): 399/401.

2, 5-dimethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ]]Phenanthren-3-yl) ethyne-2-yl]Benzyl } aminoquinoline-3-carboxylic acid methyl ester was prepared by the general procedure described above (see example 1). Melting point: more than 155 ℃; MS (ES +): m⁺+H＝751。

Example 12:

2, 5-dimethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethen-2-yl ] benzyl } aminoquinoline-3-carboxylic acid methyl ester

The product described in example 11 was hydrogenated in analogy to the procedure in example 2, to yield the title compound as light yellow solid. Melting point: > 180 ℃ (resolved) MS (ES +): m⁺+H＝756。

Example 13

2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 1- (4- (3-bromobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

a)1- (4-amino-2-methylquinolin-3-yl) ethanone was prepared in analogy to intermediate 2a, example 6, by a tin tetrachloride-promoted reaction of 2-aminobenzonitrile with acetylacetone in a manner known from the literature (Tetrahedron51(1995), 12277).

b)1- (4- (3-Bromobenzylamino) -2-methylquinolin-3-yl) ethanone was prepared from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 3-bromobenzyl bromide by the same procedure as used for the preparation of 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). Melting point: 109 ℃; MS (ES +): 369/371.

2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ]]Phenanthren-3-yl) ethyne-2-yl]Benzyl } aminoquinolines are prepared by the general procedure described above (see example 1). Melting point: 195 deg.C (decomposition); MS (ES +): m⁺+H＝721。

Example 14

2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminoquinoline

The title compound was prepared by catalytic hydrogenation of the product described in example 13 as described in example 2. Melting point: 170 ℃ (decomposition); MS (FAB +): m⁺＝725.

Example 15:

2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-N-glycylamide-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminoquinoline

The synthesis route is as follows:

a) 2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid (N-glycidylethyl) amide-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminoquinoline

55mg of the product prepared in example 14 are placed in 5ml of anhydrous DMF and a solution of 1ml of 0.1ml of triethylamine in 10ml of anhydrous DMF is added at 0 ℃.25 mg of TOTU was added, followed by stirring at 0 ℃ for 20 minutes and at room temperature for 30 minutes. The solution was added to a solution of 11mg glycine ethyl ester hydrochloride in 2ml DMF, 2ml H₂O and 1ml triethylamine and stirred at room temperature until conversion is complete. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 41mg of the corresponding ethyl ester.

b) 2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid N-glycylamide-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethan-2-yl ] benzyl } aminoquinoline

41mg of the ethyl ester obtained above was dissolved in 5ml of methanol, and 28mg of KOH in 1.5ml of H was added dropwise at room temperature₂O, and stirred at room temperature. After 2 hours, the solvent was removed and the residue taken up in 5ml of H₂In O, the desired product was precipitated by adjusting to pH 5 with dilute hydrochloric acid. The precipitate was filtered off with suction and air-dried. MS (ES +): m⁺+H：782。

Example 16

2-methyl-3- (acetyl-1-yl) -4- {3- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid N- (2-sulfonic acid) ethylamide-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminoquinoline

55mg of the product from example 14 are placed in 5ml of anhydrous DMF and a solution of 1ml of 0.1ml of triethylamine in 10ml of anhydrous DMF is added at 0 ℃.25 mg of TOTU was added, followed by stirring at 0 ℃ for 20 minutes and at room temperature for 30 minutes. Dissolving the mixture in waterThe solution was made up of 10mg taurine in 2ml DMF, 2ml H₂O and 1ml triethylamine and stirred at room temperature until conversion is complete. The solvent was removed and the residue was purified by silica gel chromatography to give 36mg of the title compound as a pale yellow solid. MS (ES +): m⁺+H：832。

Example 17

2-methyl-3- (acetyl-1-yl) -4- {2- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline

Preparing an intermediate:

see example 1

Intermediate 2: 1- (4- (3-bromobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

a)1- (4-amino-2-methylquinolin-3-yl) ethanone: see example 13(Tetrahedron51(1995), 12277).

b)4- (2-Bromobenzylamino) -2-methylquinolin-3-yl) ethanone was synthesized from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 2-bromobenzyl bromide by the same procedure as used for the preparation of 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). Melting point: 134 ℃ of; MS (ES +): 369/371.

2-methyl-3- (acetyl-1-yl) -4- {2- [1- (3 α,7 α, 12 α -trihydroxy-10Beta, 13 beta-dimethyl-17 beta- (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a]Phenanthren-3-yl) ethyne-2-yl]Benzyl } aminoquinoline is prepared from these two intermediates by the general procedure described above (see example 1). MS (ES +): m⁺+H＝721。

Example 18

2-methyl-3- (acetyl-1-yl) -4- {2- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminoquinoline

The product compound of example 17 was hydrogenated by the method in example 2 to obtain the desired product as a pale yellow solid. Melting point: 165 ℃ (decomposition); MS (ES +): 725.

example 19

4- [3 β - (2- {4- [ (3-acetyl-2-methylquinolin-4-ylamino) methyl ] benzoylamino } ethoxy) -7 α, 12 α -dihydroxy-10 β, 13 β -dimethylhexadecahydrocyclopenta [ a ] phenanthren-17 β -yl ] pentanoic acid methyl ester

Preparing an intermediate:

intermediate 1: 3 beta-O- (1-aminoeth-2-yl) cholic acid methyl ester

See example 3(Tetrahedron lett., 33(1992), 195; Tetrahedron lett., 34(1993), 817).

Intermediate 2: 4- [ (3-acetyl-2-methylquinolin-4-ylamino) methyl ] benzoic acid

The synthesis route is as follows:

a) 2-methyl-3- (acetyl-1-yl) -4- (4-bromobenzyl) aminoquinoline is described in example 1 as intermediate 2.

b)4- [ (3-acetyl-2-methylquinolin-4-ylamino) methyl ] benzoic acid

370mg of 2-methyl-3- (acetyl-1-yl) -4- (4-bromobenzyl) aminoquinoline, 79mg of triphenylphosphine and 78mg of calcium formate were dissolved in 4ml of DMF and 4ml of benzene. Under a protective atmosphere, 9mg of palladium acetate was added and the solution was heated to 120 ℃ under a CO atmosphere. After 2 hours, 58mg of tetrakis (triphenylphosphine) palladium were added and stirring was continued at 120 ℃. Stirring was continued at this temperature until no conversion could be detected. If desired, additional palladium catalyst is added. For work-up, 2N NaOH was added and the mixture was extracted with dichloromethane. The organic phase was extracted once more with 2N NaOH and the combined aqueous phases were extracted with dichloromethane. The NaOH extract was adjusted to pH 6 with 6N HCl and concentrated in vacuo. The residue was taken up in a small amount of methanol. The insoluble salt was filtered off. The filtrate was concentrated and placed in a small amount of H₂And (4) in O. The product was obtained as a yellow insoluble solid, which was filtered off with suction and air-dried. 81mg of a yellow solid are obtained. Melting point: > 210 ℃ (decomposition); MS (ES +): 335.

67mg of intermediate 2 are dissolved in 5ml of DMF and a solution of 1ml of 0.28ml of triethylamine in 10ml of DMF is added at 0 ℃. A solution of 66mg of TOTU in 2ml of DMF was added, followed by stirring at 0 ℃ for 30 minutes and at room temperature for 45 minutes. This solution was added dropwise to a solution of 93mg of intermediate 1 in 2ml of DMF and 1ml of triethylamine and stirred at room temperature until the conversion was complete. For working up, it is concentrated in vacuo, the residue is taken up in ethyl acetate, the precipitate is filtered off and washed with NaHCO₃Solution and H₂And O, washing the filtrate. The organic phase is separated off, dried over magnesium sulfate and the solvent is removed. The resulting residue was chromatographed on silica gel together with the removed precipitate to give 71mg of the product as a yellow-orange solid. Melting point: > 98 ℃ (decomposition); MS (ES +): 782.

example 20

4- [3 β - (2- {4- [ (3-acetyl-2-methylquinolin-4-ylamino) methyl ] benzoylamino } -ethoxy) -7 α, 12 α -dihydroxy-10 β, 13 β -dimethylhexadecahydrocyclopenta [ a ] phenanthren-17 β -yl ] pentanoic acid

The ester obtained in example 19 was reacted according to a hydrolysis method similar to that described in example 4 to obtain the desired product as a colorless solid. Melting point: > 145 ℃ (decomposition); MS (ES +): 768.

example 21

2-Ethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethyne-2-yl ] benzyl } aminoquinoline-3-carboxylic acid methyl ester

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 4- (4-Bromobenzylamino) -2-ethylquinoline-3-carboxylic acid methyl ester

The synthesis route is as follows:

a) methyl 4-amino-2-ethylquinoline-3-carboxylate is prepared according to methods known to the person skilled in the art (Tetrahedron51(1995), 12277).

b)4- (4-Bromobenzylamino) -2-ethylquinoline-3-carboxylic acid methyl ester is prepared by

1- (4- (4-Bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2c) was prepared in the same manner from methyl 4-amino-2-ethylquinoline-3-carboxylate and 4-bromobenzyl bromide. MS (ES +): 399/401.

Methyl 2-ethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminoquinoline-3-carboxylate was prepared by the general procedure described above (see example 1). Melting point: more than 200 ℃; ms (fab): 751.

example 22

2-Ethyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethan-2-yl ] benzyl } aminoquinoline-3-carboxylic acid methyl ester

The product described in example 21 was hydrogenated in analogy to the procedure in example 2 to yield the title compound as light yellow solid. Melting point: > 190 ℃ (decomposition); MS (ES +): 755.

example 23

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -3-fluorobenzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 1- (4- (4-bromo-3-fluorobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

a)1- (4-amino-2-methylquinolin-3-yl) ethanone; see example 13(Tetrahedron51(1995), 12277).

b)1- (4- (4-bromo-3-fluorobenzylamino) -2-methylquinolin-3-yl) ethanone was synthesized from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 4-bromo-3-fluorobenzyl bromide by the same procedure as used to prepare 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). MS (ES +): 387/389.

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -3-fluorobenzyl } aminoquinoline was prepared according to the general procedure described above (see example 1). Ms (fab): 739.

example 24

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethen-2-ylidene ] -3-fluorobenzyl } aminoquinoline

The product described in example 23 was hydrogenated in analogy to the procedure in example 2, to yield the title compound as light yellow solid. MS (ES +): 744.

example 25

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -3-chlorobenzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 1- (4- (4-bromo-3-chlorobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

b)1- (4- (4-bromo-3-chlorobenzylamino) -2-methylquinolin-3-yl) ethanone is prepared by

1- (4- (4-Bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2c) was prepared in the same manner from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 4-bromo-3-chlorobenzyl bromide. MS (ES +): 403/405.

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -3-chlorobenzyl } aminoquinoline was prepared according to the general procedure described above (see example 1). Ms (fab): 755.

example 26:

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -2-fluorobenzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 1- (4- (4-bromo-2-fluorobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

b)1- (4- (4-bromo-2-fluorobenzylamino) -2-methylquinolin-3-yl) ethanone was prepared from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 4-bromo-2-fluorobenzyl bromide by the same procedure as used to prepare 1- (4- (4-bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2 c). MS (ES +): 387/389.

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -2-fluorobenzyl } aminoquinoline was prepared according to the general procedure described above (see example 1). MS (ES +): 739.

example 27

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethen-2-yl ] -2-fluorobenzyl } aminoquinoline

The product described in example 26 was hydrogenated in analogy to the procedure in example 2, to yield the title compound as light yellow solid. MS (ES +): 744.

example 28

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -2-chlorobenzyl } aminoquinoline

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1

Intermediate 2: 1- (4- (4-bromo-2-chlorobenzylamino) -2-methylquinolin-3-yl) ethanone

The synthesis route is as follows:

b)1- (4- (4-bromo-2-chlorobenzylamino) -2-methylquinolin-3-yl) ethanone is prepared by

1- (4- (4-Bromobenzylamino) -2-methylquinolin-3-yl) ethanone (example 1, intermediate 2c) was prepared in the same manner from 1- (4-amino-2-methylquinolin-3-yl) ethanone and 4-bromo-2-chlorobenzyl bromide. MS (FAB +): 403/405.

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] -2-chlorobenzyl } aminoquinoline was prepared according to the general procedure described above (see example 1). MS (FAB +): 756.

example 29

2-methyl-3- (acetyl-1-yl) -4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] -2-chlorobenzyl } aminoquinoline

The product described in example 28 was hydrogenated in analogy to the procedure in example 2 to yield the title compound as light yellow solid. MS (ES +): 760.

example 30

2, 6-dimethyl-3-acetyl-1-yl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminopyridine

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1.

Intermediate 2: 1- [4- (4-bromobenzylamino) -2, 6-dimethylpyridin-3-yl ] ethanone

The synthesis route is as follows:

a) 3-acetyl-2, 6-dimethyl-1H-pyridin-4-one is prepared by methods known in the literature (chem. pharm. Bull., 31, 1983, 4303).

b)1- (4-chloro-2, 6-dimethylpyridin-3-yl) ethanone is synthesized by methods known to those skilled in the art (J.Heterococcus lic chem., 18, 1981, 603).

c)1- [4- (4-bromobenzylamino) -2, 6-dimethylpyridin-3-yl ] ethanone

1.0g of 1- (4-chloro-2, 6-dimethylpyridin-3-yl) ethanone was dissolved in 10ml of dimethylacetamide, and 1.5 equivalents of 4-bromobenzylamine were added. The solution was heated at 140 ℃ and 150 ℃ until no conversion could be detected. If desired, 1 equivalent of 4-bromobenzylamine is added. For work-up, the solvent was distilled off in vacuo and the residue was purified by chromatography on silica gel to give the title compound as a yellow oil. MS (ES +): 333/335.

2, 6-dimethyl-3-acetyl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminopyridine was prepared by the general procedure described above (see example 1). MS (ES +): 685.

example 31

2, 6-dimethyl-3-acetyl-1-yl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethylidene-2-yl ] benzyl } aminopyridine

The product described in example 30 was hydrogenated in analogy to the procedure in example 2 to yield the title compound as light yellow solid. MS (ES +); 689.

example 32

2-Ethyl-6-methyl-5-acetyl-1-yl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzylamino } pyridine

Preparing an intermediate:

intermediate 1: 3 beta-ethynyl cholic acid

See example 1.

Intermediate 2: 1- [4- (4-bromobenzylamino) -2-ethyl-6-methylpyridin-5-yl ] ethanone

The synthesis route is as follows:

a)2, 2-dimethyl-5-propionyl- [1, 3] dioxane-4, 6-dione is prepared according to a method known in the literature (J.org.chem., 43, 1978, 2087).

b) 3-acetyl-6-ethyl-2-methyl-1H-pyridin-4-one was prepared according to the method described in example 30 (example 30; intermediate 2a) (chem. pharm. bull., 31, 1983, 4303).

d)1- (4-chloro-6-ethyl-2-methylpyridin-3-yl) ethanone was prepared by a method known in the literature in analogy to intermediate 2b, example 30 (j. heterocyclic chemi, 18, (1981) 603).

e)1- [4- (4-Bromobenzylamino) -2-ethyl-6-methylpyridin-5-yl ] ethanone was prepared from 4-chloro-2-ethyl-6-methylpyridine and 4-bromobenzylamine by the method described in example 30 (intermediate 2 c). MS (ES +): 347/349.

2-Ethyl-6-methyl-5-acetyl-1-yl-4- {4- [1- (3 α,7 α, 12 α -trihydroxy-10 β, 13 β -dimethyl-17 β - (pentanoic acid-4-yl) hexadecahydrocyclopenta [ a ] phenanthren-3-yl) ethynyl-2-yl ] benzyl } aminopyridine was prepared by the general procedure described above (see example 1). MS (ES +): 700.

Claims

1. A compound of formula I:

wherein:

g is

K is-OR (7), -HN-CH₂-CH₂-SO₃H、-NH-CH₂-CO₂H. -Ocat, wherein cat is a cation;

r (7) is selected from hydrogen or (C)₁-C₄) -an alkyl group;

r (1) is hydrogen, -OH;

l is (C)₁-C₅) -alkyl, wherein one or more CH₂The units may be replaced by-C.ident.C-, -NH-, -CO-or-O-;

p is

R (16) -R (24) are independently selected from hydrogen, F, Cl and (C)₁-C₄) -alkyl, or is a bond to L of one of COR (25), COOR (25), and R (16) -R (24);

r (25) and R (26) are independently selected from hydrogen and (C)₁-C₄) -an alkyl group.

2. Compounds of formula I according to claim 1, wherein

G is

R (1) is hydrogen, -OH;

p is

Wherein

3. A medicament containing one or more compounds according to claim 1 or 2.

4. The medicament of claim 3, further comprising one or more lipid-lowering active ingredients.

5. A process for preparing a medicament containing one or more compounds of claim 1 or 2, comprising mixing a compound of claim 1 or 2 with a pharmaceutically acceptable carrier and formulating into a dosage form suitable for administration.

6. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the prevention or treatment of gallstones.

7. A process for the preparation of a compound according to claim 1 or 2, comprising the following reaction steps:

reacting a compound of formula IId wherein K, R (1), and R (3) -R (6) have the meanings given in formula I, with a compound of formula IIId P-X wherein P has the meaning given in formula I and X is Br or I.